Synthesis and SAR of a novel positive allosteric modulator (PAM) of the metabotropic glutamate receptor 4 (mGluR4)

This Letter describes the synthesis and SAR of the novel positive allosteric modulator, VU0155041, a compound that has shown in vivo efficacy in rodent models of Parkinson's disease. The synthesis takes advantage of an iterative parallel synthesis approach to rapidly synthesize and evaluate a number of analogs of VU0155041. (C) 2009 Elsevier Ltd. All rights reserved.

Fibre-optic strain sensor system with temperature compensation for arch bridge condition monitoring

This paper presents an innovative sensor system, created specifically for new civil engineering structural monitoring applications, allowing specially packaged fiber grating-based sensors to be used in harsh, in-the-field measurement conditions for accurate strain measurement with full temperature compensation. The sensor consists of two fiber Bragg gratings that are protected within a polypropylene package, with one of the fiber gratings isolated from the influence of strain and thus responding only to temperature variations, while the other is sensitive to both strain and temperature. To achieve this, the temperature-monitoring fiber grating is slightly bent and enclosed in a metal envelope to isolate it effectively from the strain. Through an appropriate calibration process, both the strain and temperature coefficients of each individual grating component when incorporated in the sensor system can be thus obtained. By using these calibrated coefficients in the operation of the sensor, both strain and temperature can be accurately determined. The specific application for which these sensors have been designed is seen when installed on an innovative small-scale flexi-arch bridge where they are used for real-time strain measurements during the critical installation stage (lifting) and loading. These sensors have demonstrated enhanced resilience when embedded in or surface-mounted on such concrete structures, providing accurate and consistent strain measurements not only during installation but subsequently during use. This offers an inexpensive and highly effective monitoring system tailored for the new, rapid method of the installation of small-scale bridges for a variety of civil engineering applications.

Trajectory Control of Electro Hydraulic Excavator using Fuzzy Self Tuning Algorithm with Neural Network

This paper presents the trajectory control of a 2DOF mini electro-hydraulic excavator by using fuzzy self tuning with neural network algorithm. First, the mathematical model is derived for the 2DOF mini electro-hydraulic excavator. The fuzzy PID and fuzzy self tuning with neural network are designed for circle trajectory following. Its two links are driven by an electric motor controlled pump system. The experimental results demonstrated that the proposed controllers have better control performance than the conventional controller.

Extracellular Loop 2 of the Free Fatty Acid Receptor 2 Mediates Allosterism of a Phenylacetamide Ago-Allosteric Modulator

Allosteric agonists are powerful tools for exploring the pharmacology of closely related G protein-coupled receptors that have nonselective endogenous ligands, such as the short chain fatty acids at free fatty acid receptors 2 and 3 (FFA2/GPR43 and FFA3/GPR41, respectively). We explored the molecular mechanisms mediating the activity of 4-chloro-alpha-(1-methylethyl)-N-2-thiazolylbenzeneacetamide (4-CMTB), a recently described phenylacetamide allosteric agonist and allosteric modulator of endogenous ligand function at human FFA2, by combining our previous knowledge of the orthosteric binding site with targeted examination of 4-CMTB structure-activity relationships and mutagenesis and chimeric receptor generation. Here we show that 4-CMTB is a selective agonist for FFA2 that binds to a site distinct from the orthosteric site of the receptor. Ligand structure-activity relationship studies indicated that the N-thiazolyl amide is likely to provide hydrogen bond donor/acceptor interactions with the receptor. Substitution at Leu(173) or the exchange of the entire extracellular loop 2 of FFA2 with that of FFA3 was sufficient to reduce or ablate, respectively, allosteric communication between the endogenous and allosteric agonists. Thus, we conclude that extracellular loop 2 of human FFA2 is required for transduction of cooperative signaling between the orthosteric and an as-yet-undefined allosteric binding site of the FFA2 receptor that is occupied by 4-CMTB.

Binding site of AMPA-receptor allosteric modulator

The computer molecular docking of piperonyl acid piperidide (BDP) and some its analogs already known as ampakins was conducted for estimating their possible binding with AMPA-receptor glutamate domains in cyclothiazide binding area and for further design of new structures maximally complimentary to the receptor. On the base of the conducted docking it can be suggested that the binding site of BDP (amides of benzodioxane-6-carboxylic and piperonyl acids) analogs is located in AMPA-receptor cyclothiazide binding pocket. It is shown that formation of protein-ligand complexes of AMPA-receptor with benzodioxane-6-carboxylic and piperonyl acid derivatives, similarly to cyclothiazide, proceeds with interaction with Ser497, Leu751, which significance is confirmed by site-specific mutagenesis.

Monitoring the moisture transport in building stones using fibre optic relative humidity sensors

Weathering of stone is one of the major reasons for the damage of stone masonry structures and it takes place due to interlinked chemical, physical and biological processes in stones. The key parameters involved in the deterioration processes are temperature, moisture and salt. It is now known that the sudden variations in temperature and moisture greatly accelerate the weathering process of the building stone fabric. Therefore, in order to monitor these sudden variations an effective and continuous monitoring system is needed. Furthermore, it must consist of robust sensors which are accurate and can survive in the harsh environments experienced in and around masonry structures. Although salt penetration is important for the rate of deterioration of stone masonry structures, the processes involved are much slower than the damage associated with temperature and moisture variations. Therefore, in this paper a novel fibre optic temperature cum relative humidity sensor is described and its applicability in monitoring building stones demonstrated. The performance of the sensor is assessed in an experiment comprising wetting and drying of limestone blocks. The results indicate that the novel fibre optic relative humidity sensor which is tailor made for applications in masonry structures performed well in wetting and drying tests, whilst commercial capacitance based sensors failed to recover during the drying regime for a long period after a wetting regime. That is, the fibre optic sensor has the capability to measure both sorption and de-sorption characteristics of stone blocks. This sensor is used in a test wall in Oxford and the data thus obtained strengthened the laboratory observations.

Study of reliability of fibre Bragg grating fibre optic strain sensors for field-test applications

In this paper, the reliability and thus the suitability of optical fibre strain sensors for surface strain measurement in concrete structures was investigated. Two different configurations of optical strain sensors were used each having different mountings making them suitable for different uses in various structures. Due to the very limited time available to install the sensors and take result, commercially packaged sensors were used. In the tests carried out each sensor was mounted onto a concrete beam which was then subjected to a range of known and calibrated loadings. The performance of the optical strain sensors thus evaluated was compared with the results of conventional techniques. This comparison allows for selecting the best performing combination of sensor/mounting, i.e. long-gauge sensor with mounts bolted to threaded rods glued into the concrete for use in future work in a field test where a limited time window was available for installation, testing and post-test demounting. © 2012 Elsevier B.V.